scholarly journals The Role of Phospholipase C Signaling in Macrophage-Mediated Inflammatory Response

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Liqian Zhu ◽  
Clinton Jones ◽  
Gaiping Zhang
Keyword(s):  
Inflammatory Response ◽  
Phospholipase C ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Second Messengers ◽  
Mononuclear Phagocyte ◽  
Mitogen Activated Protein Kinase ◽  
Phosphate Ester ◽  
Cellular Functions ◽  
Mitogen Activated Protein

Macrophages are crucial members of the mononuclear phagocyte system essential to protect the host from invading pathogens and are central to the inflammatory response with their ability to acquire specialized phenotypes of inflammatory (M1) and anti-inflammatory (M2) and to produce a pool of inflammatory mediators. Equipped with a broad range of receptors, such as Toll-like receptor 4 (TLR4), CD14, and Fc gamma receptors (FcγRs), macrophages can efficiently recognize and phagocytize invading pathogens and secrete cytokines by triggering various secondary signaling pathways. Phospholipase C (PLC) is a family of enzymes that hydrolyze phospholipids, the most significant of which is phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Cleavage at the internal phosphate ester generates two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), both of which mediate in diverse cellular functions including the inflammatory response. Recent studies have shown that some PLC isoforms are involved in multiple stages in TLR4-, CD14-, and FcγRs-mediated activation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and interferon regulatory factors (IRFs), all of which are associated with the regulation of the inflammatory response. Therefore, secondary signaling by PLC is implicated in the pathogenesis of numerous inflammatory diseases. This review provides an overview of our current knowledge on how PLC signaling regulates the macrophage-mediated inflammatory response.

Diacylglycerol and ceramide formation induced by dopamine D2S receptors via Gβγ-subunits in Balb/c-3T3 cells

2003 ◽  
Vol 284 (3) ◽  
pp. C640-C648 ◽  
Author(s):  
Gele Liu ◽  
Mohammad H. Ghahremani ◽  
Behzad Banihashemi ◽  
Paul R. Albert
Keyword(s):  
Cell Growth ◽  
Phospholipase C ◽  
G Protein ◽  
G Proteins ◽  
Second Messengers ◽  
Mitogen Activated Protein Kinase ◽  
Fibroblast Cells ◽  
Induced Responses ◽  
3T3 Cells ◽  
Mitogen Activated Protein

Diacylglycerol (DAG) and ceramide are important second messengers affecting cell growth, differentiation, and apoptosis. Balb/c-3T3 fibroblast cells expressing dopamine-D2S (short) receptors (Balb-D2S cells) provide a model of G protein-mediated cell growth and transformation. In Balb-D2S cells, apomorphine (EC50= 10 nM) stimulated DAG and ceramide formation by 5.6- and 4.3-fold, respectively, maximal at 1 h and persisting over 6 h. These actions were blocked by pretreatment with pertussis toxin (PTX), implicating Gi/Goproteins. To address which G proteins are involved, Balb-D2S clones expressing individual PTX-insensitive Gαiproteins were treated with PTX and tested for apomorphine-induced responses. Neither PTX-insensitive Gαi2nor Gαi3rescued D2S-induced DAG or ceramide formation. Both D2S-induced DAG and ceramide signals required Gβγ-subunits and were blocked by inhibitors of phospholipase C [1-(6-[([17β]-3-methoxyestra-1,2,3[10]-trien- 17yl)amino]hexyl)-1H-pyrrole-2,5-dione (U-73122) and partially by D609]. The similar G protein specificity of D2S-induced calcium mobilization, DAG, and ceramide formation indicates a common Gβγ-dependent phospholipase C-mediated pathway. Both D2 agonists and ceramide specifically induced mitogen-activated protein kinase (ERK1/2), suggesting that ceramide mediates a novel pathway of D2S-induced ERK1/2 activation, leading to cell growth.

scholarly journals Sin1-mediated mTOR signaling in cell growth, metabolism and immune response

2019 ◽  
Vol 6 (6) ◽  
pp. 1149-1162
Author(s):  
Chun Ruan ◽  
Xinxing Ouyang ◽  
Hongzhi Liu ◽  
Song Li ◽  
Jingsi Jin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Current Knowledge ◽  
Mammalian Target Of Rapamycin ◽  
Adaptor Protein ◽  
Interaction Network ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Functions ◽  
Evolutionarily Conserved ◽  
Mitogen Activated Protein ◽  
Growth Metabolism

Abstract The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase with essential cellular function via processing various extracellular and intracellular inputs. Two distinct multi-protein mTOR complexes (mTORC), mTORC1 and mTORC2, have been identified and well characterized in eukaryotic cells from yeast to human. Sin1, which stands for Sty1/Spc1-interacting protein1, also known as mitogen-activated protein kinase (MAPK) associated protein (MAPKAP)1, is an evolutionarily conserved adaptor protein. Mammalian Sin1 interacts with many cellular proteins, but it has been widely studied as an essential component of mTORC2, and it is crucial not only for the assembly of mTORC2 but also for the regulation of its substrate specificity. In this review, we summarize our current knowledge of the structure and functions of Sin1, focusing specifically on its protein interaction network and its roles in the mTOR pathway that could account for various cellular functions of mTOR in growth, metabolism, immunity and cancer.

CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C–dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 1959-1965 ◽  
Author(s):  
Martine J. Smit ◽  
Pauline Verdijk ◽  
Elisabeth M. H. van der Raaij-Helmer ◽  
Marjon Navis ◽  
Paul J. Hensbergen ◽  
...  
Keyword(s):  
T Cells ◽  
Phospholipase C ◽  
Inflammatory Diseases ◽  
Interferon Γ ◽  
Mitogen Activated Protein Kinase ◽  
Delayed Type Hypersensitivity ◽  
Activated T Cells ◽  
T Cell Migration ◽  
Human T Cells ◽  
Mitogen Activated Protein

Abstract The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. These interferon γ (IFNγ)–induced chemokines are thought to be crucial in directing activated T cells to sites of inflammation. As such, they play an important role in several chronic inflammatory diseases including ulcerative colitis, multiple sclerosis, artherosclerosis, and delayed-type hypersensitivity reactions of the skin. In this study, we first demonstrate that in COS-7 cells heterologously expressing CXCR3, CXCL11 is a potent activator of the pertussis toxin (PTX)–sensitive p44/p42 mitogen-activated protein kinase (MAPK) and Akt/phosphatidylinositol 3 kinase (PI3K) pathways. Next, we show that these signal transduction pathways are also operative and PTX sensitive in primary human T cells expressing CXCR3. Importantly, abrogation of these signaling cascades by specific inhibitors did not block the migration of T cells toward CXCR3 ligands, suggesting that MAPK and Akt activation is not crucial for CXCR3-mediated chemotaxis of T cells. Finally, we demonstrate that CXCR3-targeting chemokines control T-cell migration via PTX-sensitive, phospholipase C pathways and phosphatidylinositol kinases other than class I PI3Kγ.

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

2007 ◽  
Vol 293 (5) ◽  
pp. F1556-F1563 ◽  
Author(s):  
Frank Y. Ma ◽  
Greg H. Tesch ◽  
Richard A. Flavell ◽  
Roger J. Davis ◽  
David J. Nikolic-Paterson
Keyword(s):  
Inflammatory Response ◽  
P38 Mapk ◽  
Renal Injury ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Direct Role ◽  
Mitogen Activated Protein ◽  
Early Inflammatory Response ◽  
Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

scholarly journals Phosphorylation sites at the C-terminus of the platelet-derived growth factor receptor bind phospholipase C gamma 1.

1993 ◽  
Vol 4 (1) ◽  
pp. 49-57 ◽  
Author(s):  
A Kashishian ◽  
J A Cooper
Keyword(s):  
Growth Factor ◽  
Phospholipase C ◽  
Tyrosine Phosphorylation ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Phosphorylation Sites ◽  
C Terminus ◽  
Mitogen Activated Protein ◽  
Src Homology

We have identified two tyrosine phosphorylation sites, Tyr 1009 and Tyr 1021, in the C-terminal noncatalytic region of the human platelet-derived growth factor (PDGF) receptor beta subunit. Mutant receptors with phenylalanine substitutions at either or both of these tyrosines were expressed in dog epithelial cells. Mutation of Tyr 1021 markedly reduced the PDGF-stimulated binding of phospholipase C (PLC) gamma 1 but had no effect on binding of the GTPase activator protein of Ras or of phosphatidylinositol 3 kinase. Mutation of Tyr 1009 reduced binding of PLC gamma 1 less severely. Mutation of Tyr 1021, or both Tyr 1009 and Tyr 1021, also reduced the PDGF-dependent binding of a transiently expressed fusion protein containing the two Src-homology 2 domains from PLC gamma 1. Mutation of Tyr 1021, or both Tyr 1009 and Tyr 1021, greatly reduced PDGF-stimulated tyrosine phosphorylation of PLC gamma 1 but did not prevent the tyrosine phosphorylation of other cell proteins, including mitogen-activated protein kinase. We conclude that Tyr 1021, and possibly Tyr 1009, is a binding site for PLC gamma 1.

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